Degrasyn-like symmetrical compounds: possible therapeutic agents for multiple myeloma (MM-I)

Abstract

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.

Keywords: Degrasyn; Inhibitors; Jak2/Stat3; Multiple myeloma; Small molecules; Synthesis.

Figure 1

Tyrphostin, degrasyn and degrasyn like compounds

Figure 2

Anti-tumor activity of degrasyn-like commercial compounds against MM-1 cell lines. ^aFor all the compounds %inhibition determined at 10 μM.

Figure 3

Anti-tumor activity of series I compounds against MM-1 cell lines. ^aRacemic compound.

Figure 4

Anti-tumor activity of series II compounds against MM-1 cell lines.

Figure 5

Effects of WP1130 and CP2005 (8a) on Usp9xCD activity. Usp9xCD activity was assessed in the presence or absence of the indicated concentration of each compound. The rate of substrate (Ub-AMC) cleavage was measured over time by monitoring fluorescence. Compounds were incubated with enzyme for 30 min at 37 °C before the addition of substrate

Figure 6

Effect of WP1130 and CP2005 (8a) on DUB activity in Z138 cells. The activity of Usp9x (HA-Usp9x) is depicted.